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1 REVIEW ARTICLE ISSN: X J Korean Thyroid Assoc 2012 vember 5(2): 갑상선의단일유전자질환 서울대학교의과대학내과학교실 조선욱, 박영주 Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea Monogenic disorder is a single gene disorder resulted of a single mutated gene. Monogenic disorder has benefits in early diagnosis and precious prediction of disease course. Furthermore, monogenic disorder could provide an informative knowledge to the understanding of related pathophysiology. Thyroid monogenic disorder could occur in various steps, such as thyroid development, hormonogenesis, TSH-receptor signaling, thyroid hormone transport and end organ response. Here, we reviewed of congenital hypothyroidism, congenital hyperthyroidism and thyroid hormone resistance syndrome. Key Words: Monogenic disorder, Congenital hypothyroidism, Congenital hyperthyroidism, Thyroid hormone resistance syndrome 서론 현대의학에서유전자질환은가장정확하게일찍질병발생가능성을미리확인하고, 질병경과를예측할수있다는데의의가있다. 그뿐만아니라유전자질환의이해는질병의병태생리를이해하는데많은공헌을해왔다. 유전자질환으로는단일유전자질환과복합유전자질환이있다. 단일유전자질환 (monogenic disorder) 은질환의원인이 100% 유전적소인에있는경우를말하고, 복합유전자질환 (polygenic disorder) 이란유전적인자와환경인자의상호작용으로발생한질환을뜻한다. 복합유전자질환들은그종류에따라유전적인자가미치는영향이다양한데, 당뇨병, 류마티스관절염등유전적소인이중요한원인으로알려진질환을대표적인복합유전자질환으로들수있다. 복합유전자질환에서그유전적소인이차지하는비중이높을수록, 각질환의연관유전자를찾아서, 이를이용하여질환의예방, 진단및치료에이용하는소위 맞춤치료 에이용하려는노력이활발하게이루어지고있다. 갑상선질환의대표적인복합유전자질환으로는자가면역갑상선염과갑상선암등을들수있는데, 이에대해서는연구가미진한실정이다. 한편, 단일유전자변이에의하여발생하는갑상선질환은갑상선의발생, 갑상선호르몬의생성및운반, 작용, 조절기전등전반적인갑상선의작용기전및성장과연관된어떠한유전자의변이에의해서도발생할수있다 (Fig. 1). 그중대표적인단일유전자갑상선질환의종류와임상적특징, 관련유전자이상은다음 Table 1과같다. 단일유전자갑상선질환에대한이해는갑상선질환의병태생리에대한정보를축적함으로써, 단일유전자갑상선질환뿐만아니라, 복합유전자갑상선질환에대한이해와더불어새로운진단과치료법개발에응용될수있을것이다. 이논문에서는단일유전자갑상선질환중대표적질환 Received April 26, 2012 / Accepted June 25, 2012 Correspondence: Young Joo Park, MD, PhD, Department of Internal Medicine, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul , Korea Tel: , Fax: , yjparkmd@snu.ac.kr Copyright c 2012, the Korean Thyroid Association. All rights reserved. This is an open-access article distributed under the terms of the Creative Commons Attribution n-commercial License ( creativecommons.org/licenses/by-nc/3.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. 83

2 Fig. 1. Monogenic disorders of thyroid disease. Genes associated with thyroid gland development, thyroid hormone synthesis, transport, action through TSH receptor or central regulation by Hypothalamus- Pituitary-Thyroid axis could be a cause of monogenic thyroid disease. 인선천성갑상선기능저하증, 갑상선기능항진증, 그리고갑상선호르몬내성증후군에대하여간략하게살펴보았다. 선천성갑상선기능저하증 선천성갑상선기능저하증은영유아에서가장흔한내분비질환이며, 신생아에서 1:2000-1:4000의높은유병률을보인다. 병태생리학적으로는 2개아형으로분류할수있으며, 1,2) 갑상선종의유무및갑상선의위치등에따라 Fig. 2와같은아형과그원인이되는유전자변이를나누어볼수있다. 전체선천성갑상선기능저하증의 85% 를차지하는갑상선발생장애 (thyroid dysgenesis) 는갑상선의분화, 이동, 또는성장의이상과갑상선자극호르몬에대한저항성을보이는경우로서, 98% 에서는산발성, 2% 에서가족성을보이며, 갑상선의무형성또는이소성갑상선을특징으로한다. 이중 5% 의환자에서는 NKX2.1 (TTF-1, TITF1, T/EBP), FOXE1 (TTF-2, TITF2, FKHL12), PAX-8, NKX2.5 그리고 thyroid stimulating hormone (TSH) 수용체의돌연변이가밝혀져있다. 1,2) 또다른아형은갑상선호르몬생성의결함 (dyshormonogenesis) 을보이는경우로전체의 15% 를차지한다. 1) 이군은상염색체열성 (autosomal recessive) 유전 질환으로대부분갑상선호르몬결핍에의해이차적으로증가한 TSH의영향으로갑상선의크기가증가한갑상선종 (goiter) 이발견되는경우가많다. NIS (sodium iodide symporter), 3) SLC26A4 ( 다기능성 anion exchanger인 pendrin 단백유전자 ), 4) thyroperoxidase (TPO), 5) dual oxidase 2 (DUOX2), 6) DUOX mutation factor 2 (DUOXA2), 6) dehalogenase 1 (DEHAL1) 7) and thyroglobulin (Tg) 8) 등의유전자돌연변이가이와연관이있고, 이중 Tg 유전자의돌연변이가가장많이연구되어있다. Tg 유전자는 270 kb의 single copy gene으로염색체 8번의장완 (8q24.2-8q24.3) 에위치하여있으며, 8.5 kb의전사부위 (coding sequence) 를포함하고있으며, 48개의엑손 (exon) 으로나누어져있다. 9,10) Tg는갑상샘에매우특이적으로존재하는당단백으로갑상선여포세포에서생산되며, 갑상선호르몬의생합성에사용된다. 갑상선종을가진환자에서 Tg가낮은농도를보이면서과염화수소방출검사 (perchlorate discharge test) 에서정상반응을보이는경우 Tg 유전자의결함을의심해볼수있다. 현재까지 Tg 단백의구조이상의원인이되는 52개의돌연변이를보이고있으며, 이들유전자의돌연변이는정상적인갑상선호르몬생성을저해한다. 돌연변이종류를살펴보면, 재조합부위 (splicing site) 의변화 (11개), 조기종결코돈 (premature stop codon) 의생성 (11개), 아미노산변형초래 (23개), 유전자결손 Vol. 5,. 2,

3 Table 1. Classification of monogenic disorders in hypothalamus-pituitary-thyroid axis Disease Gene defeat (Inheritance) Phenotype References Thyroid development Thyroid dysgenesis PAX8 (AD) Hypothyroidism, ectopic or hypoplastic thyroid 37,38) TTF1[NKX2-1] haploinsufficiency Hypothyroidism, pulmonary hypoplasia, choreoathetosis 39,40) Thyroid agenesis Bamforth-Lazarus syndrome TTF1 (AR) Hypothyroidism, palatal clefts, spiky hair, choreoathetosis 41) Thyroid hormonogenesis Iodide transport defect NIS (AR) Hypothyroidism, goiter 42) Total organification defect TPO, THOX2 (AR) Hypothyroidism, goiter 43,44) Partial organification defect THOX2 (AD) Transient neonatal hypothyroidism 44) Pendred's syndrome PDS (AR) Goiter, sensorineural deafness 45) Thyroglobulin defect Tg (AR) Hypothyroidism, goiter 46) Tg (AD) Simple goiter 47) TSH-receptor signaling Complete TSH resistance TSH-R (AR) Hypothyroidism, thyroid hypoplasia 48) Partial TSH resistance Pseudohypoparathyroidism type 1a TSH-R (AR) Euthyroid hyperthyrotropinemia 49) GNAS1 (AD & paternal imprinting) Parathyroid hormone resistance, osteodystrophy 50) Familial gestational hyperthyroidism TSH-R (AD)[K183R] Hyperthyroidism in pregnancy 51) Hereditary toxic thyroid hyperplasia TSH-R activation (AD) Congenital hyperthyroidism 52) Toxic thyroid adenoma TSH-R activation (somatic) Autonomous follicular adenoma 53) McCune-Albright syndrome GNAS1 activation (mosaic) Polyostotic fibrous dysplasia, precocious puberty 54) Thyroid hormone transport Euthyroid hypothyroxinemia TBG (XR) TBG deficiency 55) Euthyroid, excess serum total thyroid hormones Familial dysalbuminemic hyperthyroxinemia Familial dysalbuminemic hypertriiodothyroninemia TBG duplication (XR) TBG excess 56) TTR (AD) Increased TTR affinity 57) Alb (AD) 58) Alb (AD) 59) Transmembrane defect MCT8 (XR) Low serum T4, high serum T3, psychomotor retardation, nystagmus End organ response Resistance to thyroid hormone THRB (AD) serum T4, T3, normal to high serum TSH, goiter 61) Thyroid autoimmunity Autoimmune hypothyroidism APECED syndrome, APS1 AIRE (AR) Hypoparathyroidism, hypoadrenalism, candidiasis 62) IPEX syndrome FOXP3 (XR) Immune diabetes, autoimmune enteropathy 63) Chromosomal disorder Down's syndrome Autoimmune hypothyroidism Trisomy 21 Mental retardation, cardiac anomalies, others 64-66) DiGeorge/CATCH22 syndrome Graves' disease 22q11del Cardiac outflow tract anomalies, thymic hypoplasia, 67-69) hypoparathyroidism Turner's syndrome Autoimmune hypothyroidism X0 Web neck, ovarian dysgenesis, short stature, renal and aortic root abnormalities Smith-Magenis syndrome 17p11del Mental retardation, eye anomalies, self-injury, hypothyroidism 1p terminal deletion 1p36del Mental retardation, microcephaly, large fontanelle, hearing loss, hypothyroidism 27,60) 70-72) 73,74) 75) 85 J Korean Thyroid Assoc

4 Fig. 2. Molecular genetic approaches of congenital hypothyroidism (CH). 11) PDT: perchlorate discharge test, PIOD: partial iodide organification defect (PDT<90%), TIOD: total iodide organification defect (PDT>90%), NKX2.1: also known as TTF-1, TITF1, or T/EBP, FOXE1: also known as TTF-2, TITF2 or FKHL15, PAX-8: paired box transcription factor 8, TSH: thyrotropin, TSHR: receptor for TSH, NIS: sodium iodide symporter, SLC26A4: gene encoding pendrin (also known as PDS, Pendred syndrome), a multifunctional anion exchanger, DEHAL1: iodotyrosine deiodinase, TG: thyroglobulin, TPO: thyroperoxidase, DUOX2: dual oxidase 2, DUOXA2: dual oxidase maturation factor A2. (deletion) (6개), 유전자삽입 (insertion) (1개) 의양상을보인다. 11) 가장많은빈도를보이는돌연변이위치는 p.r277x, p.c1058r, p.c1977s, p.r1511x, p.a2215d 그리고 p.r2223h이다. Tg 유전자변이에의한선천성갑상선기능저하증에서는태아기에큰갑상선종을보여초음파검사로진단이가능하다. 몇몇증례에서는임신 22-26주에초음파로태아의갑상선종을발견하고, 제대정맥채혈을통하여갑상선호르몬검사와유전자검사를통하여 TR 유전자변이에의한선천성갑상선기능저하증을진단하고, L-thyroxine을양수내로주입하여출생시정상갑상선기능과현저히감소된갑상선종의결과를얻은보고를하였다. 12,13) 하지만또다른연구에서는양수천자에서측정된 TSH의농도가부정확하다는보고가있어더많은연구가필요한실정이다. 14) 갑상선호르몬저항성증후군 (thyroid hormone resistance syndrome) 갑상선호르몬저항성증후군은 thyroid hormone resistance syndrome 혹은 resistance to thyroid hormone (rth) 등으로불리고있는데, 이는말초조직이갑상선호르몬의작용에대하여저항성을가지는질환을총칭하며, 신생아선별검사에서확인된바로는갑상선호르몬내성은 40000명의신생아중 1명의빈도에서발견된다. 1967년갑상선호르몬수용체 (TRβ) 의유전자변이가처음보고된이후, 최근까지세포막의호르몬전달단백의이상 (MCT8), 갑상선호르몬대사의이상을일으키는유전자변이 (SBP2) 가보고되고있다 (Table 2). 갑상선호르몬의작용에저항성을유발할수있는가능한기전으로는보고된유전자변이이외에도갑상선호르몬의작용기전과연관된물질과이차전령물질 (second messengers) 등다양한유전자의변이가제시 Vol. 5,. 2,

5 Table 2. Diagnosis of thyroid hormone resistance syndrome Parameters GRTH Mutations in TRβ PRTH Mutations in MCT8 Mutations in SECISBP2 TSH Total/free T4 Total/free T3 Reverse T3 TSH response to TRH TSH response to T3 inhibition Goiter Thyrotoxic signs and symptoms Neurological abnormalities /normal Impaired +++ /normal Impaired /normal Low Low ++++ /normal Low GRTH: generalized resistance to thyroid hormone, PRTH: pituitary resistance to thyroid hormone 되고있다. 갑상선호르몬수용체의유전자변이갑상선호르몬은말초조직에서세포안의갑상선호르몬수용체 (thyroid hormone receptor, TR) 를통해기능을나타낸다. 갑상선호르몬수용체는염색체 17번과 3번에있는유전자에서만들어지고, TRα와 TRβ의두종으로이루어진다. 15) 1988년, rth 환자에서 TRβ의유전자변이가처음보고된이후, 16) TRβ의점돌연변이는갑상선호르몬내성의가장흔한원인으로알려져있는데, 339개의 rth 가계의 1000명이상의환자를대상으로연구하였을때 85% 의환자에서 TRβ의유전자변이가관찰되었다. 갑상선호르몬수용체의변이에의한저항성의임상양상은매우다양한데, 이는동일한유전자변이라하더라도, 개체혹은조직마다발현정도가다르며, 장기마다분포하는갑상선호르몬수용체의아형과발현정도가다르며, 갑상선호르몬의작용기전중에필요한여러가지물질들의발현양과양상에차이가있을뿐만아니라, 갑상선호르몬자체의대사도개체혹은장기마다차이가있기때문등으로설명되고있다. 대표적으로전신적으로 TRβ유전자변이가있는경우에는상대적으로갑상선기능변화에따른증상은불분명하지만낮은지능을보이는경향이있으나, 뇌하수체의 TRβ 유전자변이영향이말초조직에비하여큰경우에는갑상선호르몬의과다에의한증상이나타나게되고, 반대로말초조직의돌연변이영향이큰경우에는임상적으로기능저하를보이게된다 (Fig. 3). TRβ 유전자변이에의한갑상선호르몬내성환자는임상적으로갑상선종, 과잉행동장애, 학습장애, 발달장애, 그리고빈맥등의증상을보이는데, 임상상이환자 마다매우다양하며, 같은유전자변이를가진경우에서도증상에개인차이가심하다. 16) 병의경과도매우다양한데, 환자대부분은정상적인성장과발달을하다가갑상선호르몬의증가와갑상선종의발현으로진단된다. 일부에서는지적, 신체적발달이상이나타난다. 과잉행동장애는대개나이가들면서호전되는양상을보인다. 갑상선종은수술을하더라도재발하는경우가종종있다. 갑상선호르몬검사는 T 4 의증가에도불구하고억제되지않은 TSH의분비를특징으로한다. 일반적으로 T 3 와 rt 3 도함께증가하여 T 3:T 4 비율은정상으로유지된다. rth는임상적으로는 TSH 생성뇌하수체종양과의감별이필요한경우가많으며, rth가의심되는경우에는유전자변이에대해검사를하는것이진단에가장도움이된다. TRβ 유전자변이는주로갑상선수용체의카르복실말단부위 (carboxyl terminus) 의 CpG가많이분포하는 3 부분 (CpG-rich hot spot) 에위치하며, T 3 와의결합력을약화시키거나보조인자 (cofactor) 들과의결합이상을초래한다. 17) 현재까지 343 가계에서돌연변이가보고되었으며, 이중 325 가계는단일염기서열이대체로아미노산변화를보였으며, 나머지가계는염기서열의결손 (deletion) 이나삽입 (insertion) 으로전사유전자암호가변경되는틀이동돌연변이 (frameshift mutation) 결과를보였다. 18) 분자생물학적으로살펴보면, TRβ의한쪽대립유전자가결손이되어단일야생형대립유전자 (wild type allele) 를가지는개체는정상임에반해변이된대립유전자 (mutant allele; mtrβ) 를가지는경우는갑상선호르몬내성으로발현하게된다. 16) 유전자결손이일어나는경우정상야생형대립유전자가보상기전으로과발현하는기전을보이거나, 유전자의양적결손에의해 87 J Korean Thyroid Assoc

6 Fig. 3. Clinical characteristics of thyroid hormone resistance syndrome (RTH). Generalized thyroid receptor (TR) β mutation tends to show mental retardation with no definite abnormality of thyroid hormonal function. When the effects of TR β mutation is dominant in pituitary rather than peripheral tissues, patients show clinical hyperthyroidism. On the contrary, the effects of TR β mutation is dominant in peripheral tissues rather than pituitary, hypothyroidism is the main clinical manifestations. 유전자의단배수결손 (haploinsufficiency) 이일어나는것은아니다. 오히려변이된대립유전자가야생형유전자의작용을방해하는우성음성돌연변이 (dominant negative) 효과가주된기전이다. 따라서 mtr을가진환자는갑상선호르몬내성이우성유전형을보이는반면, 유전자결손이원인이되는경우는열성유전형을보이게된다. 19) rth에대한효과적인치료법은아직까지없다. 일부갑상선기능의증상에따라갑상선호르몬투여를고려하기도하며, 갑상선호르몬유도체가가장효과적인치료제로사용될수있을것으로기대되고있다. 갑상선을절제한후갑상선호르몬을보충하는것은적합한 TSH 반응이나말초조직의반응을예측할수없으므로오히려증상을악화시킬수있으므로매우신중하게고려되어야한다. 동물모델로는 TRβ 유전자제거 (knockout) 마우스 (TRβKO) 와변이유전자 (mutation) 의유전자치환 (knockin) 마우스 (TRβ KI) 가있어 TRβ의생물학적기능을이해하고, 갑상선호르몬내성질환의병태생리의이해에도움을주고있다. 20) TRβ KO 마우스는 TRβ 유전자결손을가진사람의모든표현형을보인다. 이형접합체 (heterozygote) 마우스는정상표현형을보이는 반면, 동형접합제 (homozygote) 마우스는갑상선호르몬의이상과함께청각이상 (sensorineural deafness), 색각이상 (monochromatic vision) 을보여이동물모델의연구를통해 TRβ 유전자결손을가진사람에있어서시청각기능에대한면밀한검사가필요함이제시되었다. 또한, 이들동물실험을통해 TRβ1의결손은청력이상을, TRβ2의결손은색각이상의원인이될수있음을밝혔다. 심장기능을살펴보면, TRβ KO 마우스는심박수의증가를보이고이는갑상선호르몬을정상화시키는경우호전되었으며, TRα1 KO 마우스는낮은심박수를보여, 21) 갑상선호르몬의심박수에대한영향은 TRα1을통한작용임을확인하였고, 이기전으로일부의갑상선호르몬내성환자에서빈맥을보이는현상을설명할수있다. TRβ KI 마우스 (frame- shift PV 와 T337) 는우성으로유전되는 mtrβ 환자의동물모델로서이형접합체 (heterozygote) 마우스에서환자와동일한표현형을보인다. 흥미로는것은이모델의동형접합체 (homozygote) 에서전이성갑상선암의발병이나타난다는점이다. 20) 이에대해서는추후많은연구가필요하다. Vol. 5,. 2,

7 갑상선호르몬수송체의유전자변이 (thyroid hormone cell transporter defect) 갑상선호르몬수용체에는뇌, 심장, 간, 신장, 부신그리고갑상선에발현하는 monocarboxylate transporter (MCT) 8과위장관, 신장, 근육, 간, 태반등에널리발현되는 MCT10, 뇌에발현하는 organic anion-transporting polypeptide (OATP) 1C1, 간에특이적인 OATP1B1 이외에도 Na+-taurocholate cotransporting polypeptide [solute carrier family (SLC) 10A1], multidrug resistanceassociated proteins, the heterodimeric L-type amino acid transporters (LATs) 등이보고되어있다. 22) 이들중 MCT8은마우스연구를통하여뇌의시상하부와변연계에존재하며 23) 유전자변이시신경학적표현형을보임이연구된이후, 24) 사람의뇌에서도대뇌피질, 해마그리고뇌실주위에위치하며, 또한뇌조직의미세혈관 (microvessel) 에도발현되어 T3가혈액뇌장벽을통과하는데중요한역할을함이알려졌다. 25,26) MCT8 유전자의변이를가진환자에서갑상선호르몬내성을보이는유전성갑상선호르몬수송체의유전자변이 (thyroid hormone cell transporter defect) 증후군이보고된이후, 27) 갑상선호르몬이수동적인확산 (diffusion) 에의해세포내로들어간다는과거의개념에서여러종류의단백들이능동적수송체 (active transporter) 로작용해서세포마다갑상선호르몬의섭취를능동적으로조절하여, 각세포에서의갑상선호르몬의섭취가세포특이적으로조절된다는개념으로바뀌고있다. MCT8 유전자는사람성염색체 X의 X-비활성화중심으로알려진부분 (Xq13.2) 중에위치한다. 28) 6개의엑손 (exon) 과 100 kb 이상의긴첫인트론 (intron) 을포함하고있으며, SLCI6 유전자가족에속해있다. X-염색체연관유전성을보이며남성환자에서는갑상선호르몬의이상과함께운동능력의지연성발달, 수유장애, 보행장애, 언어발달장애등의신경정신발달의지연을보이고, 전신근육의근긴장저하 (hypotonia) 에의해반복되는흡인성폐렴이주된사망원인이된다. 반면, 보인자인여성에서는경한갑상선호르몬이상만이나타난다. 이러한신경학적인이상증상은갑상선호르몬의이상으로설명할수없고, 전반적인갑상선기능저하증이나기능항진증에서보이는증상과는상이하다. 이는태아기의뇌세포발달에있어서 MCT8 결핍의영향이거나또는 MCT8이갑상선호르몬이아닌아직밝혀지지않은다른물질의운반에중요한역할을할가능성이있는것으로이해되고있다. 18) 특징적인갑상선기능이상은혈청의높은 T 3 와낮은 reverse T 3 를보인다. 비록대부분환자에서 T 4 감소를보이지만, 생후수일은정상 T 4 농도를유지할수있어서신생아선별검사에는진단이안되는경우가많다. 29) 생리적인농도의 T 4 보충요법은중증의환자에서는도움이되지않으며현재까지효과적인치료법은없는실정이다. 세포의 T 3 섭취장애는유전자변이의종류에따라정도가다양하다. 현재까지보고된 12개변이중 2개의과오돌연변이 (missense mutation; Leu471Pro, Leu512 Pro), 2개의정지돌연변이 (nonsense mutation; Arg245X, Ser448X) 는 0%, F229Δ, 유전자삽입 lle189, Ala224Val 에서는 2.4-5%, 그리고나머지 5개의과오돌연변이 (S194F, V235M, R271H, L434W, L598P) 에서는 % 의 T 3 섭취율을보였다. 30) 동물모델로는 MCT8-결핍재조합 (MCT8-deficient recombinant; MCK8KO) 마우스가사람에서와같은전형적인갑상선호르몬이상을보이며, 질병의이해에많은도움을주고있다. 31) 마우스의조직내의 T 3 농도는조직마다다양성정도로관찰되었다. 이는조직마다갑상선호르몬운반단백의종류와활성이다르다는것을보여준다. 간조직의경우, MCT8 보다는다른단백을이용한호르몬운반이주로작용하기때문에높은농도의 T 3 를함유하여간조직에서갑상선호르몬과다증상 (hepatic thyrotoxicosis) 을보이게되고이로인하여 D1 (deiodinase) 요오드티로닌탈요오드화효소가증가하여 reverse T 3 의생성을촉진시킨다. 이와는반대로갑상선호르몬의섭취에 MCT8 단백을주로이용하는뇌조직에서는낮은 T 3 농도를보이고 D2 요오드티로닌탈요오드화효소가증가하여 T 3 의생성을촉진시킨다. 32) 갑상선호르몬의탈요오드대사장애 (thyroid hormone metabolism defect) 요오드티로닌탈요오드화효소는갑상선호르몬인 T 3 와 T 4 를혈중및체내에서정교하게조절하는단백이다. D1과 D2는 5'-요오드티로닌탈요오드화효소로서갑상선호르몬 T 4 를 T 3 로활성화시키고, D3는 5-탈요오드화효소로 T 4 를 rt 3 로, T 3 를 T 2 로전환하여갑상선호르몬의비활성화를유도한다. 탈요오드화효소는 selenocysteine (sec) 이라는드문단백을활성화센터에포함하고있는효소로서 selenocysteine insertion sequencing-binding protein2 (SECISBP2, SBP2) 유전자에의해합성되고, 조직마다발현의종류 89 J Korean Thyroid Assoc

8 와양이다르다. 2005년, 처음으로 SBP2 유전자의변이에의해탈요오드화효소의생성이감소되어저 T 3 증후군 (low T 3 syndrome) 을일으킨유전성질환이보고되었다. 33) 최근보고된 2개가족에서연구한결과열성유전성을보였으며, 12개의알려진탈요오드화효소합성에관계하는유전자중에 SBP2의변이만이확인되었다. 환자는전형적으로 T 4 의증가, T 3 의감소, rt 3 의증가, 그리고 TSH의경도의증가를보인다. 34) 사람 SBP2 유전자는염색체 9번의장완에위치하고 (9q22.2), 17개의엑손 (exon) 을가지고, 단백은 854개의아미노산으로이루어져있다. 33) 현재까지보고된유전자변이는 R540Q와 K438X의동종결합체를보유한아버지와인트론변이 (IVS8ds+29G->A) 를가진어머니에서나온자녀, 그리고선택적전사물 (alternative transcript) 로 26bp가엑손 (exon) 8에삽입된경우, 세종류이다. 선천성 ( 유전적 ) 갑상선기능항진증 (genetic hyperthyroidism) 유전자질환과연관된갑상선기능항진증으로는 familial nonautoimmune hyperthyroidism (FNAH), sporadic congenital nonautoimmune hyperthyroidism (SCNAH) 그리고 autonomous adenoma (AA) 를들수있다. 이들세질환은 TSH수용체유전자의활성화변이 (activating mutation) 를공통된원인으로가지고비슷한병태생리를보인다. 유전자변이에의해지속적으로활성화된 TSH 수용체는갑상선세포에서 camp를계속활성화시키고결과적으로갑상선세포의증식, 갑상선세포에서 sodium iodine symporter (NIS) 단백발현의증가와이로인한요오드섭취율의증가, 호르몬생성과분비의과다그리고, 과산화수소 (H 2O 2) 의과다생성을유발하게된다. 35) 세질환에있어서유전자변이의종류나병태생리의차이는없으나, 유전자변이의양과변이가일어난세포의범위에차이가있다. 배선돌연변이 (germline mutation) 에의해발생하는 FNAH, SCNAH 는태아기에발병하며, 전갑상선조직에광범위하게변이가일어나는특징을가지고있다. 두질환의차이는 TSH수용체활성의정도이다. SCNAH의경우 FNAH에비해 TSH 수용체활성정도가강하여증상이더심하게발현하고, 더일찍진단이된다. 35) 반면에 AA는기원이되는클론 (clone) 하나의세포에서변이가일어나양성종양을형성하게된다. 36) 유전자변이의종류에따라 TSH 수용체활성이약한경우는갑상선스캔에서는경도의열성결절양상을보이지만, 주위조직의기능이유지되면서정상갑상선기능을보인다. TSH 수용체활성이강하여어느정도의역치를넘어가게되면, 증가된갑상선호르몬에의해 TSH가억제되고이에따라종양외갑상선조직은요오드섭취율이현저하게떨어지게되며, 갑상선스캔에서는강한열성결절 (hot nodule) 만이보이는 AA로발병한다. 34) 즉, Fig. 4. Pathophysiology of congenital hypothyroidism. Congenital hypothyroidism shows diverse phenotypes according to the strength of thyroid stimulating hormone receptor (THSR), number of affected cells, and disease onset. 37) Vol. 5,. 2,

9 갑상선기능항진증등의임상상은 Fig. 4에서보여주는바와같이, 35) TSH 수용체의활성화정도, 돌연변이의발생시기및발생한갑상선의세포수등에따라다양하게나타난다. 갑상선종양을유발하는단일유전자질환 (thyroid tumor as a monogenic disease) 갑상선종양을일으키는단일유전자질환으로는가족성갑상선수질암을일으키는, RET 유전자, 갑상선과오종 / 암과갑상선염을일으키는 PTEN 유전자, 갑상선분화암을일으키는 RECQL2 유전자, Carney 증후군에동반하여갑상선선종 / 암을일으키는 PRKAR1A 유전자, 가드너증후군에동반하여갑상선유두암을일으키는 APC 유전자등이있다. 결론 이상에서단일유전자돌연변이에의하여발생하는갑상선질환에대하여살펴보았다. 갑상선질환에있어유전자변이가알려진지는매우오래되었으나현재도이분야의연구는꾸준히이루어지고있고, 유전자질환의연구를통하여갑상선질환의병태생리에대한이해도를넓히는결과를얻고있다. 이러한유전자질환에관한지식의축적은, 질환의병태생리에대한정보를제공함과동시에, 최근급속히발달하고있는유전자기술과함께성인개체에대한선별검사나신생아, 영유아시기의신속하고정확한선별검사에도움을줄수있을것으로기대되고있으며, 일부표적유전자를대상으로한질환의예방및약물개발시도에응용될수있을것으로기대되고있다. 특히갑상선질환에대한연구는아직도많은부분이미제로남아있어, 새로운지속적인연구가필요한실정이다. 중심단어 : 단일유전자질환, 선천성갑상선기능저하증, 선천성갑상선기능항진증, 갑상선호르몬내성증후군. References 1) Park SM, Chatterjee VK. Genetics of congenital hypothyroidism. J Med Genet 2005;42(5): ) Rastogi MV, LaFranchi SH. Congenital hypothyroidism. Orphanet J Rare Dis 2010;5:17. 3) Spitzweg C, Morris JC. Genetics and phenomics of hypothyroidism and goiter due to NIS mutations. Mol Cell Endocrinol 2010;322(1-2): ) Bizhanova A, Kopp P. Genetics and phenomics of Pendred syndrome. Mol Cell Endocrinol 2010;322(1-2): ) Ris-Stalpers C, Bikker H. Genetics and phenomics of hypothyroidism and goiter due to TPO mutations. Mol Cell Endocrinol 2010;322(1-2): ) Grasberger H. Defects of thyroidal hydrogen peroxide generation in congenital hypothyroidism. Mol Cell Endocrinol 2010;322(1-2): ) Moreno JC, Visser TJ. Genetics and phenomics of hypothyroidism and goiter due to iodotyrosine deiodinase (DEHAL1) gene mutations. Mol Cell Endocrinol 2010;322(1-2): ) Targovnik HM, Esperante SA, Rivolta CM. Genetics and phenomics of hypothyroidism and goiter due to thyroglobulin mutations. Mol Cell Endocrinol 2010;322(1-2): ) Baas F, van Ommen GJ, Bikker H, Arnberg AC, de Vijlder JJ. The human thyroglobulin gene is over 300 kb long and contains introns of up to 64 kb. Nucleic Acids Res 1986;14(13): ) Malthiery Y, Lissitzky S. Primary structure of human thyroglobulin deduced from the sequence of its 8448-base complementary DNA. Eur J Biochem 1987;165(3): ) Targovnik HM, Citterio CE, Rivolta CM. Thyroglobulin gene mutations in congenital hypothyroidism. Horm Res Paediatr 2011;75(5): ) Caron P, Moya CM, Malet D, Gutnisky VJ, Chabardes B, Rivolta CM, et al. Compound heterozygous mutations in the thyroglobulin gene (1143delC and 6725G-->A [R2223H]) resulting in fetal goitrous hypothyroidism. J Clin Endocrinol Metab 2003;88(8): ) Pardo V, Rubio IG, Knobel M, Aguiar-Oliveira MH, Santos MM, Gomes SA, et al. Phenotypic variation among four family members with congenital hypothyroidism caused by two distinct thyroglobulin gene mutations. Thyroid 2008;18(7): ) Ribault V, Castanet M, Bertrand AM, Guibourdenche J, Vuillard E, Luton D, et al. Experience with intraamniotic thyroxine treatment in nonimmune fetal goitrous hypothyroidism in 12 cases. J Clin Endocrinol Metab 2009;94(10): ) Schwartz HL, Lazar MA, Oppenheimer JH. Widespread distribution of immunoreactive thyroid hormone beta 2 receptor (TR beta 2) in the nuclei of extrapituitary rat tissues. J Biol Chem 1994;269(40): ) Hayashi Y, Janssen OE, Weiss RE, Murata Y, Seo H, Refetoff S. The relative expression of mutant and normal thyroid hormone receptor genes in patients with generalized resistance to thyroid hormone determined by estimation of their specific messenger ribonucleic acid products. J Clin Endocrinol Metab 1993;76(1): ) Weiss RE, Weinberg M, Refetoff S. Identical mutations in unrelated families with generalized resistance to thyroid hormone occur in cytosine-guanine-rich areas of the thyroid hormone receptor beta gene. Analysis of 15 families. J Clin Invest 1993;91(6): ) Refetoff S, Dumitrescu AM. Syndromes of reduced sensitivity to thyroid hormone: genetic defects in hormone receptors, cell 91 J Korean Thyroid Assoc

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